US2009186410A1PendingUtilityA1

Rna silencing compositions and methods for the treatment of huntington's disease

54
Assignee: UNIV MASSACHUSETTSPriority: Jul 7, 2006Filed: Jan 5, 2009Published: Jul 23, 2009
Est. expiryJul 7, 2026(expired)· nominal 20-yr term from priority
Inventors:Neil AroninPhillip D. Zamore
C12N 15/111C12N 2310/14C12N 2310/3515C12N 15/113C12N 2320/34
54
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present invention relates to the discovery of an effective treatment for a variety of Huntington's disease (HD). The present invention utilizes RNA silencing technology (e.g. RNAi) against single nucleotide polymorphisms (SNPs) in the Huntingtin (htt) gene encoding the dominant, gain-of-function mutant Huntington protein, thereby resulting in an effective treatment for the gain-of-function disease.

Claims

exact text as granted — not AI-modified
1 . A method of silencing a target mRNA encoding a mutant huntingtin (htt) protein in a cell, comprising contacting the cell with effective amount of a RNA silencing agent targeting a heterozygous single nucleotide polymorphism (SNP) within the target mRNA, such that RNA silencing of said mRNA occurs, wherein the SNP has an allelic frequency of at least 35% in a sample population. 
     
     
         2 . The method of  claim 1 , wherein the SNP is present at genomic site RS362331. 
     
     
         3 . The method of  claim 3 , wherein the target mRNA comprises the sequence set forth as SEQ ID NO: 5. 
     
     
         4 . The method of  claim 3 , wherein the target mRNA comprises the sequence set forth as SEQ ID NO: 6. 
     
     
         5 . The method of  claim 3 , wherein the RNA silencing agent is capable of inducing discriminatory RNA silencing. 
     
     
         6 . The method of  claim 3 , wherein the antisense strand of said RNA silencing agent is complementary to the SNP and wherein said RNA silencing agent is capable of substantially silencing the mutant huntingtin protein without substantially silencing the corresponding wild-type huntingtin protein. 
     
     
         7 . The method of  claim 3 , wherein the sample population is of Western European origin. 
     
     
         8 . A method of silencing a target mRNA encoding a mutant huntingtin (htt) protein in a cell, comprising contacting the cell with effective amount of a siRNA targeting a heterozygous single nucleotide polymorphism (SNP) within the target mRNA, such that RNA silencing of said mRNA occurs, wherein the siRNA is selected from the group consisting of:
 a. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 3 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 4 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification;   b. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 7 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 8 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification,   c. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 9 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 10 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification, and   d. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 13 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 14 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification.   
     
     
         9 . The method of any of  claim 7 , wherein the siRNA comprises a lipophilic moiety. 
     
     
         10 . The method of  claim 9 , wherein the lipophilic moiety is a cholesterol moiety. 
     
     
         11 . An RNA silencing agent comprising an antisense strand comprising about 16-25 nucleotides homologous to a region of an mRNA encoding a mutant huntingtin (htt) protein, said region comprising a heterozygous single nucleotide polymorphism (SNP) having an allelic frequency of at least 35% in a sample population, wherein the RNA silencing agent is capable of directing RNA silencing of said mRNA. 
     
     
         12 . The RNA silencing agent of  claim 11 , wherein the SNP is present at genomic site RS362331. 
     
     
         13 . The RNA silencing agent of  claim 11 , wherein the target mRNA comprises the sequence set forth as SEQ ID NO: 5. 
     
     
         14 . The RNA silencing agent of  claim 11 , wherein the target mRNA comprises the sequence set forth as SEQ ID NO: 6. 
     
     
         15 . The RNA silencing agent of  claim 11 , which is capable of inducing discriminatory RNA silencing. 
     
     
         16 . The RNA silencing agent of  claim 11 , which is capable of substantially silencing the mutant huntingtin protein without substantially silencing the corresponding wild-type huntingtin protein. 
     
     
         17 . The RNA silencing agent of  claim 11 , wherein the RNA silencing agent is an siRNA. 
     
     
         18 . The siRNA of  claim 17 , comprising a sense strand having a nucleotide sequence identical to the sequence of the SNP. 
     
     
         19 . The siRNA of  claim 11 , wherein the sense strand of the siRNA is identical to the polymorphism at a nucleotide position that is 10 nucleotides from the 5′ end of the sense strand. 
     
     
         20 . The siRNA of  claim 11 , wherein the sense strand of the siRNA is identical to the polymorphism at a nucleotide position that is 16 nucleotides from the 5′ end of the sense strand. 
     
     
         21 . An siRNA is selected from the group consisting of:
 a. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 3 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 4 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification;   b. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 7 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 8 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification,   c. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 9 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 10 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification, and   d. an siRNA comprising (i) a sense strand comprising the sequence set forth as SEQ ID NO: 13 or a variant thereof; and (ii) an antisense strand comprising the sequence set forth as SEQ ID NO: 14 or a variant thereof, said variant comprising at least one nucleotide analog or backbone modification.   
     
     
         22 . The siRNA of  claim 21 , wherein the siRNA comprises a lipophilic moiety. 
     
     
         23 . The siRNA of  claim 22 , wherein the lipophilic moiety is a cholesterol moiety.

Join the waitlist — get patent alerts

Track US2009186410A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.